Histones, nuclear proteins that bind DNA and form nucleosomes, are directly involved with both
the packaging of DNA into chromosomes and the regulation of transcription. Histone
acetylation/deacetylation is a major factor in regulating chromatin structural dynamics during
transcription.
NCBI Summary:
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family and is a component of the histone deacetylase complex. It also interacts with retinoblastoma tumor-suppressor protein and this complex is a key element in the control of cell proliferation and differentiation. Together with metastasis-associated protein-2, it deacetylates p53 and modulates its effect on cell growth and apoptosis. [provided by RefSeq, Jul 2008]
General function
Cell death/survival, Anti-apoptotic, DNA Replication, Enzyme, Hydrolase, Nucleic acid binding, DNA binding, Transcription factor
, Epigenetic modifications
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Cellular localization
Cytoplasmic, Nuclear
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Ovarian function
Follicle development, Antral follicle growth, Follicle atresia, Steroid metabolism, Luteolysis, Oogenesis, Oocyte maturation, Early embryo development
, Pluripotent cell derivation
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HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation. Ma P et al. (2016) Oocyte and preimplantation embryo development entail dynamic changes in chromatin structure and gene expression, which are regulated by a number of maternal and zygotic epigenetic factors. Histone deacetylases (HDACs), which tighten chromatin structure, repress transcription and gene expression by removing acetyl groups from histone or non-histone proteins. HDAC1 and HDAC2 are two highly homologous Class I HDACs and display compensatory or specific roles in different cell types or in response to different stimuli and signaling pathways. We summarize here the current knowledge about the functions of HDAC1 and HDAC2 in regulating histone modifications, transcription, DNA methylation, chromosome segregation, and cell cycle during oocyte and preimplantation embryo development. What emerges from these studies is that although HDAC1 and HDAC2 are highly homologous, HDAC2 is more critical than HDAC1 for oocyte development and reciprocally, HDAC1 is more critical than HDAC2 for preimplantation development.Cell Death and Differentiation advance online publication, 15 April 2016; doi:10.1038/cdd.2016.31.//////////////////
HDAC inhibitor prevents LPS mediated inhibition of CYP19A1 expression and 17β-estradiol production in granulosa cells. Mehta A et al. (2015) LPS inhibits CYP19A1 expression and 17β-estradiol (E2) production in granulosa cells (GCs). This is one of the major causes of infertility underlying postpartum uterine infections. However, the precise molecular mechanism is not well elucidated. Recently we have shown, buffalo GCs exposed to LPS (1.0 μg/ml) in serum free culture, transiently increased the pro-inflammatory cytokine genes (IL-1β, TNF-α, IL-6) expression, followed by the inhibition of CYP19A1 expression and E2 production. The present study showed that transient increase in pro-inflammatory cytokines was associated with HDACs (gene expression and nuclear activity). Therefore, we tested the hypothesis if Trichostatin A (TSA), a HDAC inhibitor, can attenuate LPS induced pro-inflammatory cytokine gene expression and can prevent LPS mediated down-regulation of CYP19A1 expression and E2 in GCs. Results showed that TSA pre-treatment significantly attenuated LPS induced pro-inflammatory cytokine gene expressions, HDACs (both gene expression and enzyme activity in nucleus) and NF-κB nuclear translocation. Additionally, TSA pre-treatment reversed the inhibitory effect of LPS on CYP19A1 expression and E2 production. CHIP analyses of H3 (Lys 9/14) acetylation of ovary specific CYP19A1 proximal promoter (PII) showed that TSA pre-treatment prevented the LPS mediated H3 deacetylation, thereby increased the acetylation of PII and restored CYP19A1 expression and E2 production. The present study demonstrated that TSA pre-treatment attenuated- LPS induced immune response involving NF-κB and HDACs, and thus prevented inhibition of CYP19A1 expression and E2 production through chromatin remodeling. Our study suggests that HDAC inhibitors could be a potential therapeutic strategy to treat infertility underlying postpartum uterine infections.//////////////////
Histone Deacetylase 1 Down-Regulation on Developmental Capability and Histone Acetylation in Bovine Oocytes and Parthenogenetic Embryos. Wang Z et al. Histone deacetylase 1 (HDAC1) is one of the most conserved enzymes present in the nuclei of cells, including bovine oocytes and pre-implantation embryos. However, the biological functions of HDAC1 in supporting the growth and development of bovine oocytes and embryos are still not fully elucidates. In this study, three siRNAs (si299, si672, and si1272) targeting to HDAC1 mRNA sequence were designed. After transfection into bovine fibroblast cells, si299, the most effective one in HDAC1 knock-down, was selected. The selected siRNA was microinjected into bovine germinal vesicle (GV) stage oocytes to determine the functions of HDAC1 in the maturation of bovine oocytes. Finally, the siRNA was microinjected into mature oocytes, which were then parthenogenetically activated and cultured in vitro until the blastocyst stage. The rates of cleavage, blastocyst development and acetylation of lysine 14 of H3 (H3K14) state were checked. The results suggest that HDAC1 knock-down in oocytes did not influence the rates of maturation or cleavage of parthenogenetic embryos. However, the rates of blastocyst decreased after siRNA microinjection. Furthermore, histone H3K14 acetylation level increased after siRNA microinjection into parthenogenetic embryos.
\Prostaglandin F2{alpha} Suppresses Rat Steroidogenic Acute Regulatory Protein Expression via Induction of Yin Yang 1 Protein and Recruitment of Histone Deacetylase 1 Protein. Liu Q et al. Prostaglandin F2alpha (PGF2alpha) plays a pivotal role in ovarian luteolysis by inhibiting the expression of StAR protein leading to a decrease in intracellular cholesterol transport and luteal steroid production. Previously we have demonstrated that the transcription factor YY1 bound to three regions in the StAR promoter in vitro and repressed promoter activity. This study further defined the YY1-mediated PGF2alpha effect on the inhibition of StAR protein expression through YY1 interaction with a single region in the StAR promoter in vivo. PGF2alpha consistently suppressed StAR mRNA and protein expression in cultured luteal cells in a dose dependent manner. PGF2alpha also enhanced YY1 protein expression and binding to its cis-element in a time-dependent pattern that preceded the decline in StAR protein levels. The StAR promoter region bound by YY1 was also associated with histone deacetylase 1 (HDAC1). PGF2alpha treatment promoted HDAC1 binding to and suppressed the histone H3 acetylation in this region. On the contrary, YY1 knockdown decreased HDAC1 binding, increased histone H3 acetylation, enhanced StAR protein expression, and negated PGF2alpha effect on StAR protein expression. Luciferase assays showed that YY1 overexpression inhibited StAR promoter activity and the addition of a HDAC inhibitor, Trichostatin A, abrogated the effect of YY1. Trichostatin A-treated luteal cells displayed increased StAR protein expression. These data indicate that PGF2alpha enhances a direct YY1/StAR promoter interaction and the recruitment of HDAC1 to the promoter, thereby preventing transcriptional activation of the StAR gene.
Expression regulated by
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Ovarian localization
Oocyte
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Segev H, et al 2001 reported the expression patterns of histone deacetylases in bovine oocytes
and early embryos, and the effect of their inhibition on embryo
development.
Gene expression at the onset of bovine embryogenesis is developmentally
regulated and histone deacetylases (HDACs) have been shown to play a key role
in the control of gene expression during this period of development. The authors determined expression pattern(s) of powerful repressors, namely
histone deacetylase-1, -2 and -3, that may in part regulate gene expression
during bovine oogenesis and early embryogenesis at the mRNA and protein
levels. Detected fragments of the hdac genes were sequenced and comparison of
the sequences showed very high homologies between DNA and amino acid sequences
of bovine HDACs and those of human and mouse.
Effects of In Vitro Maturation on Histone Acetylation in Metaphase II Oocytes and Early Cleavage Embryos. Wang N et al. In vitro maturation (IVM) of oocyte is an effective procedure for avoiding ovarian hyperstimulation syndrome in patients with polycystic ovaries (PCOS) during in vitro fertilization (IVF). To investigate the influences of IVM on epigenetic reprogramming and to search for the possible reasons for the lower rates of fertilization and cleavage in IVM oocytes, we examined the expression of two enzymes controlling histone acetylation, histone acetyltransferase GCN5 (GCN5) and histone deacetylase 1 (HDAC1), as well as their common target, acetyl-histone H3 (Ac-H3), in mouse metaphase II (MII) oocytes and preimplantation embryos. Results showed that IVM downregulated the protein expression of GCN5 in MII oocytes and two-cell embryos and changed the distribution of GCN5 in two-cell embryos. Expression of HDAC1 mRNA in MII oocytes and two-cell embryos decreased in the IVM group. However, none of these changes persisted after two-cell embryos. Levels of Ac-H3 in both oocytes and embryos remained unchanged after IVM. Our studies indicated that IVM could affect the protein and gene expression related to histone acetylation in oocytes and early cleavage embryos. By function of selection, parts of the changes could be recovered in late embryo development.
Follicle stages
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Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment: Compensatory functions of histone deacetylase 1 (HDAC1) and HDAC2 regulate transcription and apoptosis during mouse oocyte development. Ma P et al. Dramatic changes in chromatin structure and histone modification occur during oocyte growth, as well as a global cessation of transcription. The role of histone modifications in these processes is poorly understood. We report the effect of conditionally deleting Hdac1 and Hdac2 on oocyte development. Deleting either gene has little or no effect on oocyte development, whereas deleting both genes results in follicle development arrest at the secondary follicle stage. This developmental arrest is accompanied by substantial perturbation of the transcriptome and a global reduction in transcription even though histone acetylation is markedly increased. There is no apparent change in histone repressive marks, but there is a pronounced decrease in histone H3K4 methylation, an activating mark. The decrease in H3K4 methylation is likely a result of increased expression of Kdm5b because RNAi-mediated targeting of Kdm5b in double-mutant oocytes results in an increase in H3K4 methylation. An increase in TRP53 acetylation also occurs in mutant oocytes and may contribute to the observed increased incidence of apoptosis. Taken together, these results suggest seminal roles of acetylation of histone and nonhistone proteins in oocyte development.
Species: mouse
Mutation name: type: null mutation fertility: infertile - ovarian defect Comment: A DNMT3A2-HDAC2 Complex Is Essential for Genomic Imprinting and Genome Integrity in Mouse Oocytes. Ma P et al. (2015) Maternal genomic imprints are established during oogenesis. Histone deacetylases (HDACs) 1 and 2 are required for oocyte development in mouse, but their role in genomic imprinting is unknown. We find that Hdac1:Hdac2(-/-) double-mutant growing oocytes exhibit global DNA hypomethylation and fail to establish imprinting marks for Igf2r, Peg3, and Srnpn. Global hypomethylation correlates with increased retrotransposon expression and double-strand DNA breaks. Nuclear-associated DNMT3A2 is reduced in double-mutant oocytes, and injecting these oocytes with Hdac2 partially restores DNMT3A2 nuclear staining. DNMT3A2 co-immunoprecipitates with HDAC2 in mouse embryonic stem cells. Partial loss of nuclear DNMT3A2 and HDAC2 occurs in Sin3a(-/-) oocytes, which exhibit decreased DNA methylation of imprinting control regions for Igf2r and Srnpn, but not Peg3. These results suggest seminal roles of HDAC1/2 in establishing maternal genomic imprints and maintaining genomic integrity in oocytes mediated in part through a SIN3A complex that interacts with DNMT3A2.//////////////////